Differentiation of naive CD8 T cells to memory cells after antigenic stimulation is an essential process for establishing long lasting protective immunity against viruses, intracellular bacteria, and tumors. During this differentiation process, memory CD8 T cells acquire novel properties that are distinct from their naive CD8+ T cell precursors, including the ability to mount a rapid and robust response upon antigen re-encounter. Substantial progress has been made in the past decade in understanding the phenotypic and functional characteristics of naive and memory CD8 T cells. However, the molecular mechanisms responsible for the enhanced responsiveness of memory T cells are unknown. To understand the molecular basis for the rapid and robust memory T cell responses, we analyzed gene expression profile at the whole genome scale of naive and memory CD8 T cells. Overall, we identified seventy-two genes or transcripts that were differentially expressed in memory CD8 T cells and twenty-one genes and transcripts that were differentially expressed in naive CD8 T cells from assessing over 30,000 unique genes and transcripts Based on their known functions, these differentially expressed genes were further divided into six groups: 1) Cell adhesion, 2) Cell proliferation, 3) Signal transduction, 4) Immune response, 5) Structure and metabolism, and 6) Regulation of transcription. Together, these findings provide a transcriptional basis for some unique features of memory CD8 T cells; although the roles of the majority of those memory cell differentially expressed genes in memory cell response remain to be determined. To further elucidate the basis for differential gene expression, we assessed the role of histone H3K9 acetylation (H3K9) in differential gene expression. Strikingly, higher H3K9 acetylation levels were detected in resting memory cells, prior to their activation, for those genes that were differentially expressed following activation, indicating that hyperacetylation of histone H3K9 may play a role the selective and rapid gene expression of memory CD8+ T cells. Consistent with this model, we showed that inducing high levels of H3K9 acetylation resulted in an increased expression in naive cells of those genes that are normally expressed differentially in memory cells. Together, these findings suggest that differential gene expression mediated at least in part by histone H3K9 hyperacetylation may be responsible for the rapid and robust memory CD8+ T cell response.